U.S. patent application number 13/256844 was filed with the patent office on 2012-03-08 for buccal and/or sublingual therapeutic formulation.
This patent application is currently assigned to Lingual Conseqna Pty Ltd.. Invention is credited to Alistair Cumming, David Kannar, Lance Sparrow.
Application Number | 20120058962 13/256844 |
Document ID | / |
Family ID | 43355588 |
Filed Date | 2012-03-08 |
United States Patent
Application |
20120058962 |
Kind Code |
A1 |
Cumming; Alistair ; et
al. |
March 8, 2012 |
BUCCAL AND/OR SUBLINGUAL THERAPEUTIC FORMULATION
Abstract
A buccal and/or sublingual formulation comprising one or more
active compounds; and a buccal matrix which releases the active
compounds at a predetermined rate for transport across the buccal
and/or sublingual membranes, wherein the rate of release of the
active compounds is either (A) the same or substantially the same
rate at which the active compounds are transported across the
buccal and/or sublingual membranes; or (B) a rate which releases
the active compounds over an extended period as required by the
therapeutic affect or treatment window for those active
compounds.
Inventors: |
Cumming; Alistair;
(Mornington Vic, AU) ; Sparrow; Lance; (Glen Iris
Vic, AU) ; Kannar; David; (Mt Eliza Vic, AU) |
Assignee: |
Lingual Conseqna Pty Ltd.
Collington, Victoria
AU
|
Family ID: |
43355588 |
Appl. No.: |
13/256844 |
Filed: |
May 20, 2010 |
PCT Filed: |
May 20, 2010 |
PCT NO: |
PCT/AU2010/000594 |
371 Date: |
September 15, 2011 |
Current U.S.
Class: |
514/26 ;
514/255.04; 514/419; 514/569; 514/570; 514/62; 514/653; 514/772;
514/777 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61K 9/2018 20130101; A61K 9/0056 20130101; A61K 9/2031
20130101 |
Class at
Publication: |
514/26 ; 514/569;
514/570; 514/653; 514/419; 514/62; 514/255.04; 514/772;
514/777 |
International
Class: |
A61K 31/704 20060101
A61K031/704; A61K 31/137 20060101 A61K031/137; A61K 31/4045
20060101 A61K031/4045; A61K 47/10 20060101 A61K047/10; A61K 31/495
20060101 A61K031/495; A61K 47/08 20060101 A61K047/08; A61K 47/36
20060101 A61K047/36; A61K 47/40 20060101 A61K047/40; A61K 31/192
20060101 A61K031/192; A61K 31/7008 20060101 A61K031/7008 |
Foreign Application Data
Date |
Code |
Application Number |
May 20, 2009 |
AU |
2009902280 |
Claims
1. A buccal and/or sublingual formulation comprising: (a) one or
more active compounds; and (b) a matrix which releases the active
compounds at a predetermined rate for transport across the buccal
and/or sublingual membranes, the matrix comprising one or more
compounds selected predominantly from the group consisting of: (i)
taste masking agents, (ii) enhancers, (iii) complexing agents, and
mixtures thereof; and (c) other pharmaceutically acceptable
carriers and/or excipients, wherein the rate of release of the
active compounds is either (A) the same or substantially the same
rate at which the active compounds are transported across the
buccal and/or sublingual membranes; or (B) a rate which releases
the active compounds so as to provide a higher area under the curve
(AUC) value when compared with equivalent compounds in a swallow
formulation on a dose normalised basis.
2. A buccal and/or sublingual formulation according to claim 1
wherein the matrix comprises one or more compounds selected from
the group consisting of PEGs, chitosan, hyaluronic acid,
cyclodextrins, polyalcohols, and mixtures thereof.
3. A buccal and/or sublingual formulation according to claim 1
wherein: (a) the one or more active compounds comprises one or more
compounds selected from the group consisting of naproxen,
ibuprofen, venlafaxine, glucosamine, cetirizine, melatonin,
sterolin, pharmaceutically acceptable salts thereof,
pharmaceutically acceptable derivatives thereof and mixtures
thereof; (b) the matrix comprises one or more compounds selected
from the group consisting of carbomer, lecithin, sodium
bicarbonate, spearmint, stevia, sorbitol, mannitol, caramel
flavour, Plasdone S630, ethanol powder, magnesium hydroxide,
aluminium hydroxide, citric acid, Miraculin, hyaluronic acid,
lysalbinic acid, PGA Base B, blackcurrant powder and mixtures
thereof and (c) the other pharmaceutically acceptable carriers
and/or excipients comprises one or more compounds selected from the
group consisting of PEGs 3300 to 4500, magnesium stearate,
erythritol, lactose, methyl cellulose and mixtures thereof.
4. A method for reducing the amount of active compound used to
achieve an effect in an individual patient as compared to a typical
compound that is swallowed, the method comprising administering to
an individual a buccal and/or sublingual formulation comprising (a)
one or more active compounds; and (b) a matrix which releases the
active compounds at a predetermined rate for transport across the
buccal and/or sublingual membranes, the matrix comprising one or
more compounds selected predominantly from the group consisting of:
(i) taste masking agents, (ii) enhancers, (iii) complexing agents,
and mixtures thereof; and (c) other pharmaceutically acceptable
carriers and/or excipients, wherein the rate of release of the
active compounds is either (A) the same or substantially the same
rate at which the active compounds are transported across the
buccal and/or sublingual membranes; or (B) a rate which releases
the active compounds so as to provide a higher area under the curve
(AUC) value when compared with equivalent compounds in a swallow
formulation on a dose normalised basis.
Description
FIELD OF THE INVENTION
[0001] The invention relates to a delivery system which provides
improved delivery of therapeutic compounds. In particular, the
present invention relates to buccal and sublingual
formulations.
BACKGROUND OF THE INVENTION
[0002] In this specification, where a document, act or item of
knowledge is referred to or discussed, this reference or discussion
is not an admission that the document, act or item of knowledge or
any combination thereof was at the priority date, publicly
available, known to the public, part of common general knowledge;
or known to be relevant to an attempt to solve any problem with
which this specification is concerned.
[0003] It is known that the action of a therapeutic compound can be
modified using specific excipients in the delivery formulation. In
addition, the formulation itself is often critical to the efficacy
of the compound to be delivered. One class of agents which has been
used for this purpose is the polyethylene glycols (PEGs). An
example of disclosure of a formulation using PEGs in this manner is
international patent application no WO 2006/105615. However, known
formulations using PEGs to date have not provided optimum control
of the active compound release rate to provide a range of onsets of
action (ie, from slow to rapid).
[0004] The ability to effectively deliver therapeutic compounds to
animals and, in particular, humans is frequently dependent on
compliance of the recipient. Poor patient compliance is a
significant barrier to the completion of prescription regimens and
the cause of sub-optimal clinical outcomes. Compliance is also
often connected to or associated with the formulation used to
deliver the compound. It is known that many orally delivered active
compounds also deliver either an unsatisfactory taste in the mouth
or generate burning in the throat. For these reasons, such
compounds presently have to be swallowed prior to breakdown of the
matrix and release of the active. Managing problematic taste and
other sensations are thus important for patient compliance.
[0005] Accordingly, in addition to the need to be able to control
the release rate, the buccal and/or sublingual delivery of many of
the current commercially available oral active compounds has not
been pursued because of their offensive or unpalatable taste,
unpleasant mouth feel due to chalkiness, grittiness, dryness or
astringency, low solubility in saliva or poor bioavailability.
[0006] There is a continual need to develop more improved drug
delivery formulations which: [0007] efficaciously deliver
therapeutic agents quickly yet without inducing unwanted side
effects; and/or [0008] reduce the side-effects that impact on
patient compliance; and/or [0009] provide improved control of the
release rate within a range (from slow to rapid) of onsets of
action, by using a variety of enhancers and complexing agents
(individually or in combination) to provide that tighter
control.
SUMMARY OF THE INVENTION
[0010] It has been found that a composition comprising at least one
active compound with selected excipients, complexing agents, and/or
carriers can provide improved solubility and permeability to
improve the release kinetics of the active compound(s) (when
delivered either sublingually or buccally) and increase delivery of
the active compound(s). This results in more reproducible plasma
profiles and a better managed onset of clinical effect by reason of
higher bioactivity, that is, an improved pharmacokinetic profile
for the active compound as measured by standard testing parameters
(eg: T.sub.max, C.sub.max and AUC ("area under the curve", a
measure of drug concentration) values in their known forms).
[0011] The term "buccal and/or sublingual formulation" as used
herein refers to a drug delivery formulation wherein an active
compound is provided for absorption across one or more membranes in
the buccal cavity, including the buccal mucosa, buccal gingiva,
mucous membrane of the tongue, sublingual membrane and the soft
palate. The term encompasses all suitable solid and semi-solid
dosage forms, including troches, sublingual tablets, and buccal
tablets (i.e. a preparation which can be placed under the tongue).
The term "buccal" is used in its broadest sense to refer to the
oral cavity as a whole.
[0012] The present invention is expected to provide a tailored
matrix which is capable of being modified to either: [0013] release
an active compound(s) at the same, or substantially the same, rate
at which the active compound(s) are transported across the buccal
and/or sublingual membranes to ensure the rapid balanced transport
into the bloodstream and thus deliver higher bioactivity; or [0014]
release an active compound(s) over an extended period for those
active compounds which require longer therapeutic affect windows
(or extended AUC's). (Without being bound by theory, the active
compound(s) may also be transported into the buccal or sublingual
membrane to be released over an extended period of time, ie the
membrane acts as a "reservoir".)
[0015] According to a first aspect of the invention, there is
provided a buccal and/or sublingual formulation comprising: [0016]
(a) one or more active compounds; and [0017] (b) a matrix which
releases the active compounds at a predetermined rate for transport
across the buccal and/or sublingual membranes, the matrix
comprising one or more compounds selected predominantly from the
group consisting of: [0018] (i) taste masking agents, [0019] (ii)
enhancers, [0020] (iii) complexing agents, and [0021] mixtures
thereof; and [0022] (c) other pharmaceutically acceptable carriers
and/or excipients, wherein the rate of release of the active
compounds is either (A) the same or substantially the same rate at
which the active compounds are transported across the buccal and/or
sublingual membranes; or (B) a rate which releases the active
compounds so as to provide a higher area under the curve (AUC)
value when compared with equivalent compounds in a swallow
formulation on a dose normalised basis.
[0023] A person skilled in the art will understand that the
transport in (A) above can be either passive transport or active
transport assisted by means of the influence of an agent such as a
permeation enhancer. This rate of transport in (A) can also be
further increased using a combination of effects delivered by
different excipients within the matrix. For example: [0024]
changing the pH will improve solubility of some salts. [0025]
increasing the rate of disintegration of the matrix will release
more active more quickly at the membrane interface. [0026] if the
transport rate of the active is slower than the release rate, then
it is important to also use a permeation enhancer to increase the
rate at which the active compound passes through the membrane.
[0027] A person skilled in the art will understand that the higher
AUC in (B) above can be achieved in different ways using a
combination of effects delivered by different excipients within the
matrix. For example, [0028] an earlier onset of action (when
compared with a typical swallow formulation) can be achieved by
increasing membrane permeability and thus facilitating an even
faster uptake of the active; [0029] releasing the active compound
over an extended period can be achieved by complexing the active
compound to retard release as required by the therapeutic affect
window for that active compound.
[0030] It will be appreciated by those skilled in the art that a
particular excipient may perform more than one function. For
example, an enhancer may facilitate a higher uptake rate and also
provide a taste masking effect or a sweetener/flavour may improve
palatability and act to reduce throat catch.
[0031] A person skilled in the art will understand that the
selection of appropriate active compounds (such as specific salts
or derivatives thereof) for use in a formulation according to the
invention can partly alleviate solubility issues. A person skilled
in the art will also understand that the "equivalent compounds in a
swallow formulation" in (B) above refers to compounds having the
same active core as the active compounds in the formulation
according to the invention, however the active compounds used in a
formulation according to the invention may be a different salt or
derivative thereof.
[0032] Additionally, it is important to understand that the active
compounds must then be matched with a range of enhancers to provide
the predetermined release rate, in addition to taste masking agents
to negate taste issues. When matched appropriately, the
predetermined T.sub.max, C.sub.max and AUC may be achieved.
[0033] Reference herein to an "active compound" or "biologically
active compound" includes a therapeutic or prophylactic agent,
drug, pro-drug, drug complex, drug intermediate, diagnostic agent,
enzyme, medicine, plant extract, herbal extract, infusion or
concoction, phytochemical, protein, antibody, antibody fragment or
derivative, bioactive compound or dietary supplement.
[0034] The term "matrix" as used herein refers to a solid or
semi-solid monolithic material containing one or more dissolved or
dispersed active compounds closely associated with a surrounding,
rate-controlling heterogenous material where the active compound or
compounds exhibit a zero- or first-order release rate when the
matrix is placed in direct contact with a moist diffusion membrane.
The solid or semi solid monolithic material can include a range of
materials known in the art of pharmaceutical drug delivery to taste
mask, emulsify, solubilize, complex or enhance delivery of any
biologically active lipophilic or hydrophilic compound across a
membrane.
[0035] The term "taste masking agents" when used herein refers to
taste receptor blockers, compounds which mask the chalkiness,
grittiness, dryness and/or astringent taste properties of an active
compound, compounds which reduce throat catch as well as compounds
which add a flavour. The following are examples: [0036] Taste
receptor blockers include Kyron T-134, a glycoprotein extract
called miraculin from the fruit of the plant synsepalum dulcificum,
ethyl cellulose, hydroxypropyl methylcellulose, arginine, sodium
carbonate, sodium bicarbonate, gustducin blockers and mixtures
thereof [0037] Compounds which mask the chalkiness, grittiness,
dryness and/or astringent taste properties of an active compound
include those of a natural or synthetic fatty type or other
flavorant such as cocoa, chocolate (especially mint chocolate),
cocoa butter, milk fractions, vanillin butter fat, egg or egg
white, peppermint oil, wintergreen oil, spearmint oil and similar
oils. [0038] Compounds which reduce throat catch include
combinations of high and low solubility acids. For example high
solubility acids suitable for use here include amino acids (eg
alanine, arginine etc), glutaric, ascorbic, malic, oxalic,
tartaric, malonic, acetic, citric acids and mixtures thereof. Low
solubility acids suitable for use include oleic, stearic and
aspartic acids plus certain amino acids such as glutamic acid,
glutamine, histidine, isoleucine, leucine, methionine,
phenylalanine, serine, tryptophan, tyrosine, valine and fumaric
acid. Actual amounts used will vary depending on the amount of
throat catch or burn exhibited by the active used but will
generally be in the range of 1-40%. [0039] Flavouring agents
include sweeteners and flavours. Examples of suitable sweeteners
and flavours include mannitol, sorbitol, maltitol, lactitol,
isomaltitol, erythritol, xylitol, sucrose, ammonium
glycyrrhizinate, mango aroma, black cherry aroma, sodium citrate,
colloidal silicium dioxide, sucralose; zinc gluconate; ethyl
maltitol; glycine; acesulfame-K; aspartame; saccharin; acesulfam K,
neohesperidin DC, thaumatin, stevioside, fructose; xylitol; honey;
honey extracts; corn syrup, golden syrup, misri, spray dried
licorice root; glycerrhizine; dextrose; sodium gluconate; stevia
powder; glucono delta-lactone; ethyl vanillin; vanillin; normal and
high-potency sweeteners or syrups or salts thereof and mixtures
thereof. Other examples of appropriate flavouring agents include
coffee extract, mint; lamiacea extracts; citrus extracts; almond
oil; babassu oil; borage oil; blackcurrant seed oil; canola oil;
castor oil; coconut oil; corn oil; cottonseed oil; evening primrose
oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil;
palm oil; palm kernel oil; peanut oil; grapeseed oil; safflower
oil; sesame oil; shark liver oil; soybean oil; sunflower oil;
hydrogenated castor oil; hydrogenated coconut oil; hydrogenated
palm oil; hydrogenated soybean oil; hydrogenated vegetable oil;
hydrogenated cottonseed and castor oil; partially hydrogenated
soybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate;
glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate;
glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate;
glyceryl tricaprylate/caprate; glyceryl
tricaprylate/caprate/laurate; glyceryl
tricaprylate/caprate/linoleate; glyceryl
tricaprylate/caprate/stearate; saturated polyglycolized glycerides;
linoleic glycerides; caprylic/capric glycerides; modified
triglycerides; fractionated triglycerides; safrole, citric acid,
d-limonene, malic acid and phosphoric acid or salts and/or mixtures
thereof.
[0040] The term "enhancers" when used herein refers to agents which
work to increase membrane permeability and/or work to increase the
solubility of a particular active. Both issues can be pivotal to
the properties of the formulation. The following are examples.
[0041] Chelators: EDTA, citric acid, sodium salicylate,
methoxysalicylates. (See Senel & Hincal: JCR 72 2001 133-144;
Malhalingam et al: AAPS Pharmascitech 2007 (8) vol 3 Article 55).
[0042] Surfactants: sodium lauryl sulphate, polyoxyethylene,
POE-9-laurylether, POE-20-cetylether, benzalkonium chloride,
23-lauryl ether, cetylpyridinium chloride, cetyltrimethyl ammonium
bromide, amphoteric and cationic surfactants. [0043] Membrane
disrupting compounds such as powdered alcohols (eg menthol and
ethanol), and compounds such as lipophilic enhancers which are safe
to be used orally. (Nicolazzo, Reid and Finnin J Pharmaceutical
Sciences Vol 93, No 8 Aug. 2004 2054-2063). [0044] Fatty and other
acids: oleic acid, capric acid, lauric acid, lauric acid/propylene
glycol, methyloleate, ysophosphatidylcholine, phosphatidylcholine
(Sudhakar et al JCR 114 (2006) 15-40), oleic acid co-delivered with
PEG 200, (Lee and Kellaway Int J Pharmaceutics 204 (2000) 137-144).
[0045] Lysalbinic acid (Starokadomdkyy & Dubey Int J
Pharmaceutics 308 (2006) 149-154). [0046] Non-surfactants such as
unsaturated cyclic ureas. [0047] Others: glucosaminoglycans (GAGs),
aprotinin, azone, cyclodextrin, dextran sulfate, curcumin, menthol,
polysorbate 80, sulfoxides and various alkyl glycosides. [0048]
Chitosan-4-thiobutylamide, chitosan-4-thiobutylamide/GSH,
chitosan-cysteine, chitosan-(85% degree N-deacetylation),
poly(acrylic acid)-homocysteine, polycarbophil-cysteine,
polycarbophil-cysteine/GSH, chitosan-4-thioethylamide/GSH,
chitosan-4-thioglycholic acid. Hyaluronic acid in 3 MW's (Sandri et
al: J Pharmacy and Pharmacology 2004, 56: 1083-1090.) [0049] Bile
Salts (Dihydroxy and Trihydroxy), sodium glycocholate, sodium
deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium
taurodeoxycholate(Artusi et al: Int J Pharmaceutics 250 (2003)
203-213). [0050] Propanolol hydrochloride (Akbari et al: Il Farmaco
59 (2004)155-161).
[0051] The selection of the glucoaminoglycans (GAGs) and the amount
used will depend on the active compound(s) to be included in the
formulation. A person skilled in the art will be able to select a
suitable GAG to achieve the predetermined pharmacokinetics for a
particular active ingredient because the properties of GAGs are
well known. For example, GAGs such as chitosan and hyaluronic acid
exhibit a higher swelling profile and slower erosion rate producing
sustained release characteristics. It is known in public art that
GAGs have the ability to influence bioequivalence. --Mar. Drugs
2010, 8: 1305-1322[17]. The term "complexing agents" when used
herein includes agents in the group consisting of: [0052]
Cyclodextrins. Cyclodextrins are obtained from the enzymatic
hydrolysis of starch and, depending on the enzyme used, the Alpha
(6 glucose units), Beta (7 glucose units) or Gamma (8 glucose
units) forms are obtained, which differ in the diameter of the
circle and, therefore, may form complexes with products having a
higher or lower molecular weight. The most widely used is
beta-cyclodextrin, which is composed of 7 glucose units cyclically
bonded to form a ring. When these complexes are formed, the
functional group responsible for a product's bad taste may become
"blocked" by the new bonds formed. [0053] There are other compounds
in the market with a high number of hydroxyl groups that are used
in pharmaceutical processes, such as other carbohydrates like
glucose, mannose or galactose, or polyalcohols derived from these
carbohydrates, such as mannitol or sorbitol. The most widely known
application of these polyalcohols, more specifically, of mannitol
and sorbitol, in pharmacy is mainly as diluents in pharmaceutical
forms in powder or tablets, both for humid granulation of the
mixtures and for direct compression. They are very widely used in
the manufacturing of sugar-substitute chewable tablets, since they
are not cariogenic and they provide fewer calories to the final
product. Mannitol and sorbitol may also be used as plasticisers for
the gelatin used in soft-gelatin capsules adapted to contain active
principles; and also as crystallisation inhibitors in sugar syrups.
In addition, mannitol is also used as a lyophilisation excipient
because it favours the sublimation process. Many of these compounds
have the advantage of also being taste masking agents. [0054]
Buffering materials can be both used to increase solubility and
enhance adsorption of active compounds. Examples of suitable
buffering materials or antacids suitable for use herein comprise
any relatively water-soluble antacid acceptable to the Food &
Drug Administration, such as aluminum carbonate, aluminum hydroxide
(or as aluminum hydroxide-hexitol stabilized polymer, aluminum
hydroxide-magnesium hydroxide co-dried gel, aluminum
hydroxide-magnesium trisilicate codried gel, aluminum
hydroxide-sucrose powder hydrated), aluminum phosphate, aluminum
hydroxy carbonate, dihydroxyaluminum sodium carbonate, aluminum
magnesium glycinate, dihydroxyaluminum aminoacetate,
dihydroxyaluminum aminoacetic acid, bismuth aluminate, bismuth
carbonate, bismuth subcarbonate, bismuth subgallate, bismuth
subnitrate, calcium carbonate, calcium phosphate, hydrated
magnesium aluminate activated sulfate, magnesium aluminate,
magnesium aluminosilicates, magnesium carbonate, magnesium
glycinate, magnesium hydroxide, magnesium oxide and magnesium
trisilicate, and or mixtures thereof. Preferred buffering materials
or antacids include aluminum hydroxide, calcium carbonate,
magnesium carbonate and mixtures thereof, as well as magnesium
hydroxide. Many of these compounds have the advantage of also being
taste masking agents particularly useful for addressing throat
catch. [0055] the group consisting of amphoteric surfactants,
cationic surfactants, amino acids having nitrogen functional groups
and proteins rich in these amino acids.
[0056] A person skilled in the art would understand that the
buffering agents are modifying the pH of the formulation to
minimise damage to the mucosal membranes, for example, by an acidic
active compound.
[0057] Preferred complexing or enhancing agents include PEGs,
chitosan, hyaluronic acid, cyclodextrins and polyalcohols. It
should be noted that preference for a complexing agent is primarily
governed by the specific requirements of the active to be
delivered.
[0058] The selection of the other excipients, such as permeation
enhancers, disintegrants, masking agents, binders, flavours,
sweeteners and taste maskers, is specifically matched to the active
depending on the predetermined pharmacokinetic profile and/or
organoleptic outcome.
[0059] A person skilled in the art will understand that the term
"active compounds" includes approved pharmaceutical ingredients
(API).
[0060] The invention relates to a formulation which can be used
with a wide range of active compounds and combinations of active
compounds. Whilst each active ingredient will have its own
characteristics, these characteristics will be known to the person
skilled in the art and that person will be able to easily develop a
formulation according to the invention. Further, it is common for
some active ingredients to be administered together as they have a
complementary or synergistic effect.
[0061] Examples of suitable active compounds include but are not
limited to anti-infective agents (antibiotics), eye, ear, nose and
throat preparations, anti-neoplastic agents including antibody,
nanobody, antibody fragment(s), antibody directed enzyme pro-drug
therapy (ADEPT), gastrointestinal drugs, respiratory agents,
arthritic agents, antihistamines, anti-emetics, blood formation and
coagulation agents, diagnostic agents, hormones and synthetic
substitutes, cardiovascular drugs, (including but not limited to
fibrinolytics, hypocholesterolaemic and hyperlipidaemia agents,
platelet thinning agents), hypothyroidism drugs, psychoactive
drugs, immunotherapy agents, skin and mucous membrane preparations,
NSAIDs, analgesics, anaesthetics (including but not limited to
pre-anaesthetics and post-analgesics especially where nausea and
vomiting limit oral administration), muscle spasm medications,
anti-inflammatory agents, central nervous system drugs, dietary
supplements, plant extracts, photosensitizing agents,
hyposensitizing agents, heterodimers, monomers, oligomers,
homodimers, diabetic agents, and electrolyte and water balance
agents as single actives, salts, mixtures, pain relief agents,
ibuprofen, ketaprofen, acetaminophen/paracetamol, diclofenac,
opoids, proteins, peptides, pro-drugs, drug complexes, drug
intermediates, vitamins and minerals, derivatives, enzyme or
protein and protein complexes including but not limited to
vaccines.
[0062] Other active compounds include for example a bisphosphonic
acid or a bisphosphonate salt, CoQ10, immunotherapy and
anti-allergy agents, hormones of natural or synthetic (also known
as bioidentical) origin, insulin, triamcinolone, testosterone,
levonorgestrel, estradiol, phytoestrogen, estrone, dexamethasone,
ethynodiol, prednisone, desogestrel, cyproterone, norethindrone,
megestrol, hydrocortisone, danazol, cetirizine, levocetirizine
dihydrochloride, statins, cox-2 inhibitors, expectorants,
dextromethorphan, cortisone acetate, aviane, nandrolone,
fluoxymesterone, fludrocortisone, fluoxymesterone dexamethasone,
levora fludrocortisone, low-ogestrel methylprednisolone, necon,
estropipate, levoxyl, methimazole, propylthiouracil desmopressin,
zolpidem, pentosan polysulfate, progesterone, prednisolone,
orgestrel, trivora, venlafaxine, hydrochloride, zovia, black elder
berry extracts (sambucus nigra), gestodene, alfacalcidol,
1,25-dihydroxyvitamin D3, clomiphene, finasteride and tibolone or
any biologically relevant intermediate or a combination of two or
more of any of the above-mentioned agents especially where
vomiting, nausea or other clinical parameters limit oral
administration. Preferred bisphosphonic acids or bisphonate salts
are selected from the group comprising alendronate, etidronate,
pamidronate, tiludronate, risedronate and alendronate compounds.
Even more preferably, the bisphosphonic acid is alendronate
selected from the group comprising anhydrous alendronate or
hydrated alendronate salts, such as sodium alendronate.
[0063] The formulation also includes other pharmaceutically
acceptable carriers and/or excipients such as binders, lubricants,
diluents, coatings, disintegrants, barrier layer components,
glidants, colouring agents, solubility enhancers, gelling agents,
fillers, proteins, co-factors, emulsifiers, solubilising agents,
suspending agents and mixtures thereof.
[0064] A person skilled in the art would know what other
pharmaceutically acceptable carriers and/or excipients could be
included in the formulations according to the invention. The choice
of excipients would depend on the characteristics of the
compositions and on the nature of other pharmacologically active
compounds in the formulation. Appropriate excipients are known to
those skilled in the art (see Handbook Of Pharmaceutical
Excipients, fifth edition, 2005 edited by Rowe et al., McGraw
Hill). For example Maize starch might act as a binder, a diluent
and as a disintegrating agent.
[0065] Examples of appropriate other excipients include: [0066]
suspending agents to improve texture and consistency selected from
the group consisting of tetragonolobus, Acacia glaucophylla, Acacia
abyssinica, Acacia nilotica, Acacia gummifera, Acacia arabica,
silica gel, kollidon, cremaphor, kollicoat, solutol, ludipress and
mixtures thereof. [0067] lubricants such as magnesium stearate,
stearic acid, sodium stearyl fumarate and mixtures thereof. [0068]
microcrystalline cellulose, crosslinked sodium
carboxymethylcellulose, silica, Aerosil 200, corn starch, and
mixtures thereof. [0069] coatings. [0070] a binding and gelling
agent such as hydroxypropyl methocellulose (HPMC). [0071] a
colouring agent which may be a dye or a pigment. Suitable colouring
agents are well known in the art and include curcumin, carotenoids,
sunset yellow, tartrazine, indigo dyes, quino-phthalene dyes and
triphenyl methane dyes. [0072] antiflatulents such as simethicone,
bulking agents such as polydextrose, antioxidants such as butylated
hydroxyl toluene. [0073] PEG-fatty acid esters with surfactant. The
higher the molecular weight of the PEG used, the slower the
formulation will dissolve. In addition, a molecular weight below
2500 is difficult to use in powder tablet equipment. Preferably,
for a dry powder process producing a quick release formulation, the
PEG molecular weight is between 3000 to 4000. Suitable PEG-fatty
acid esters include those with a molecular weight up to 8000 and
the fatty acid component can be selected from any suitable fatty
acid such as laurate, dilaurate, oleate, stearate, glycerol
trioleate, dioleate, glyceryl laurate, glyceryl oleate, palm kernel
oil, hydrogenated castor oil, caster oil, corn oil,
caprate/caprylate glycerides, polyglyceryl-10 laurate,
phytosterols, cholesterol, soya sterol, sorbitan oleate and
sorbitan laurate. Other examples of suitable PEGs include
polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl
ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl
ether, tocopheryl PEG-100 succinate, polyglyceryl-10 oleate, Tween
40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose
monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl
phenol series, a poloxamer, and mixtures thereof. The PEG can be
selected to alter pharmacokinetics of the buccal matrix in a way to
achieve either a zero or first order release rate depending upon
the drug application. One skilled in the art of pharmaceutical drug
delivery will appreciate that the selection of various alternative
matrices will also alter the kinetics of the drug release across
the buccal mucosa.
[0074] The selection of the PEG or PEG derivative and the amount
used will depend on the active compound(s) to be included in the
formulation. A person skilled in the art will be able to select a
suitable PEG or PEG derivative to achieve the predetermined
pharmacokinetics for a particular active ingredient because the
properties of PEGs are well known. In particular, it has been known
for some time that a low molecular weight PEG is usually a liquid
whereas a higher molecular weight PEG tends to be a waxy solid.
[0075] It is also known that PEGs can complex with other compounds.
Examples of such complexation include pegylation and PEG-fatty acid
esters. These PEG complexes have different properties to the PEG
alone which are useful when used in the present invention. For
example, some pure uncomplexed PEGs having a molecular weight below
2000 floculate or exist as a liquid gel at room temperature which
can make it difficult to use in a dry powder tabletting process. In
contrast, the complexes of these low molecular weight PEGs are able
to be used in a dry powder tabletting process. A person skilled in
the art will know the properties of the different PEGs and PEG
derivatives and be able to select the appropriate one to use with
the selected active ingredient to provide the predetermined
pharmacokinetics.
[0076] There are some doubts in the pharmaceutical industry
regarding the use of PEG because of its associated carcinogenic
potential due to trace contaminants. It is possible to use other
excipients, such as chitosan and hyaluronic acid (which will
deliver the same or a similar effect as PEG), should this be a
concern.
[0077] Generally, the buccal and/or sublingual formulation
according to the invention is capable of releasing the active
compounds from within seconds to within hours and, more preferably,
within at least about 60 minutes and, even more preferably, within
about 40 minutes. Most preferably the buccal and/or sublingual
formulation should be dissolved within 5 to 20 minutes but be
capable of delivering drugs over an extended period.
[0078] The buccal and/or sublingual formulations of the present
invention are expected to reduce the severity of gastrointestinal
side-effects of particular active compounds. Symptoms of
gastrointestinal irritation include indigestion, pain, nausea,
vomiting, cramps, haemorrhaging, kidney damage, liver damage,
diarrhoea and flatulence.
[0079] For example, the formulation according to the invention is
expected to remove the need for the addition of esomeprazole, a
potent proton pump inhibitor (PPI), added to some formulations to
minimise the formation of gastric ulcers caused by the long-term
use of NSAID for osteoarthritis patients.
[0080] The present invention further contemplates methods of
treatment and/or prophylaxis of medical conditions in mammals and,
in particular, humans by the administration of a drug delivery
formulation which enhances the bioavailability of the drug, its
salts or its metabolic derivatives, pro-drugs, intermediates or
complexes. The expression "in need of" includes a subject directly
requiring the formulation as well as situations where there is a
perceived need to provide the formulation or where prophylaxis is
required.
[0081] For example, there is a perceived need to develop a
formulation having a prophylactic action to reduce the onset of
Parkinson's disease. The Heart Research Institute is investigating
using acetaminophen to inhibit the production of myeloperoxidase
and the Harvard Medical School is investigating ibuprofen.
Formulations according to the invention could be developed for
these active compounds for use in these prophylactic
treatments.
[0082] According to a further aspect of the invention there is
provided a method for reducing the amount of compound necessary to
achieve an effect in an individual as compared to a typical
compound that is swallowed. The method comprises providing the
buccal dosage forms of the present invention to an individual to
achieve a specific effect. The buccal dosage form requires less
than the typical amount of compound generally used in other
formulations to achieve the effect. The buccal dosage form is
placed in contact with the buccal membrane to thereby cause the
compound to be released and absorbed optimally through the mucous
membranes in a buccal cavity of the individual.
[0083] The formulation may be constructed in a manner known to
those skilled in the art so as to give the predetermined controlled
release of the compound. Typically, a formulation for a specific
active compound will involve a multi step approach. By way of
example, it may be that for a particular active compound, the issue
of poor solubility (important for dissolution in the oral cavity)
is addressed by pH adjustment or the addition of an enhancer or by
altering the active compound by using its salt or some other
derivative of the active compound. The same active compound might
also exhibit poor membrane permeability and therefore require the
addition of an enhancer to the formulation. It might also be
possible to alter the structure of the active compound in different
ways to facilitate its active transport across the buccal mucosa.
Finally, the active compound, when released from the matrix, may
exhibit an unacceptable taste. This would then require the
inclusion of a suitable taste masking agent in the formulation.
Where speed of onset is not considered a major factor, it may be
viable to consider complexing the active compound, as an
alternative to mask any taste, using a fatty acid or other
compounds that may otherwise reduce membrane uptake of the
bioactive compound or complex. A well known fact to one skilled in
the art is that some complexation alternatives, while functioning
effectively as taste maskers, also retard the uptake rate of the
active.
[0084] In one embodiment, the buccal and/or sublingual delivery
system is manufactured using a dry manufacturing process with all
the components blended in a normal dry powder process and
compressed using a standard tabletting machine. Such dry
formulations can be manufactured in commercial numbers and provided
in conventional blister packaging. This process is applicable where
the excipients are chosen to eliminate the need for any wet
formulation or semi manual processing which are costly and time
intensive.
DRAWINGS
[0085] Various embodiments/aspects of the invention will now be
described with reference to the following drawings in which,
[0086] FIG. 1 shows the In Vitro Dissolution Data from Example
1.
[0087] FIG. 2 shows the Mean Concentration Time Profile data from
Example 1.
[0088] FIG. 3 shows the Mean Dose Normalised (to 100 mg)
Concentration-Time Profiles from Example 1.
[0089] FIG. 4 sets out the Pharmacokinetic Parameter Results from
Example 1.
[0090] FIG. 5 sets out the Summary Pharmacokinetic Parameters from
Example 1.
[0091] FIG. 6 shows the Dose Normalised Data from Example 3.
[0092] FIG. 7 shows the Dose Normalised AUC Values from Example
3.
[0093] FIG. 8 shows the ideal dose normalised curve for
ibuprofen.
[0094] FIG. 9 shows the venlafaxine blood plasma levels obtained in
the prior art.
[0095] FIG. 10 shows the expected blood plasma levels for the
formulation from Example 4 compared with those of the prior
art.
EXAMPLES
[0096] Various embodiments/aspects of the invention will now be
described with reference to the following non-limiting
examples.
Example 1
[0097] This example investigated the pharmacokinetics (T.sub.max,
C.sub.max and AUC) of naproxen to determine the effect of certain
variables on the plasma drug levels [1]. In particular, the
pharmacokinetics of an orally ingested commercially available
tablet form (Naprogesic.RTM. Bayer) containing 275 mg of naproxen
sodium were compared with those of a compounded buccal matrix
containing either 100 mg naproxen sodium or 100 mg naproxen. The
trials were carried out on a total of 9 patients of various ages,
weights and gender.
[0098] As the bioavailability of orally delivered naproxen is high
[2], it was not anticipated that, in this case, there will be any
major benefit in bioavailability seen from the use of a buccal
system. However, buccal delivery may be capable of achieving the
same bioavailability as oral delivery but with a lower loading dose
of the active compound. In addition, by-passing the
gastrointestinal tract will eliminate the classic gastrointestinal
problems [1,3] associated with oral delivery and then first pass
metabolism in the liver.
[0099] A second aim of the study was to compare the
pharmacokinetics of a formulation containing a naproxen salt (i.e.
sodium) as the active versus a similar formulation containing
naproxen base as the active. There is a significant difference in
solubility between the two forms of naproxen [4]. Figures quoted
for naproxen base and naproxen sodium solubility in phosphate
buffer are 6.8 mg/ml for naproxen base and 200 mg/ml for the sodium
salt [5]. Such a large difference in solubility gives rise to the
expectation of a difference in the pharmacokinetics for the two
different forms.
Method:
[0100] The study was an open label, pharmacokinetic investigation
in small group (n=9) of subjects of mixed gender and age. The order
of the study was not randomised. In each case, a single dosage form
was studied with plasma concentrations of naproxen determined over
a dosage interval. Following a 1 week minimum wash out period, the
subject was administered the alternative dosage form and again the
naproxen plasma concentration was monitored over a dosage
interval.
Selection of Study Population
[0101] Subjects were healthy men and women of variable age who all
met the inclusion and exclusion criteria as defined below.
[0102] Inclusion Criteria: [0103] In good health [0104] Aged
between 35 and 70 years old [0105] Body mass index between 20-35
[0106] Capable of providing informed consent
Exclusion Criteria:
[0106] [0107] Regular use of pain controlling medication or abuse
of alcohol or any drugs [0108] Medical problems that could affect
pharmacokinetics
Treatments:
[0109] Two dosage forms were used during the trial--oral and
buccal. The buccal was made available in two forms one having the
active present as the base and the other as the sodium salt.
[0110] Oral--Commercially available naproxen sodium was used. The
selected tablet was a Naprogesic.RTM. tablet manufactured for Bayer
Australia (equivalent compound in a swallow formulation). These
tablets contained 275 mg Naproxen present in the tablet as the
sodium salt.
[0111] Buccal--formulations according to the present invention were
prepared as per the table below. The formulations contained the
equivalent of 100 mg naproxen either present as the naproxen sodium
salt or naproxen base. Solubility trials on the formulations showed
that both formulations dissolved in 20 to 30 minutes.
TABLE-US-00001 % of the Total by weight Component Naproxen base
Naproxen sodium Magnesium Stearate <2% <2% (Flowing agent)
Sorbitol (binder and up to 42% .sup. up to 42% .sup. solubility
enhancer) PEG 4500 (release agent) 15% 15% Lactose (binder) 20% 20%
Flavour (Blackcurrant powder) <0.1%.sup. <0.1%.sup. Stevia
(sweetener) 0.4 1.6% Sodium bicarbonate 0.50%.sup. 0.50%.sup.
(disintegrant accelerator and masking agent) Naproxen base (Active)
20% -- Naproxen sodium (Active) -- 21.30% Sorbitol fulfilled
different functional roles including as a binder, a solubility
enhancer and it can mask some of the milder bitter tasting actives.
PEG 4500 was used to enable a dry powder process and the
predetermined rate of release of the naproxen. The stevia content
was varied slightly reflecting the difference in taste bitterness
between the base (0.4% Stevia) and the salt (much worse) which had
1.6% Stevia as a sweetener. Sodium bicarbonate is another
multi-function excipient which affects the rate of dissolution as
well as being an effective taste masker.
[0112] Samples of both the commercial tablet and the compounded
buccal matrix were assayed to confirm naproxen contents. All were
within 3% of the target dose.
Blood Analytical Methodology:
Blood Sample Preparation
[0113] The following preparation procedure (based on established
methodology) was used for the samples [0114] Weigh tube and record
weight [0115] Mix tube [0116] Centrifuge for 5 minutes at 3000 rpm
[0117] Remove 1 ml of plasma and place into centrifuge tube [0118]
Add 2 ml of acetonitrile and mix well [0119] Centrifuge for 5
minutes at 3000 rpm [0120] Extract 1 ml of clear supernatant for
chromatographic analysis.
Analytical Procedure
[0121] Chromatographic analysis was carried out using commercially
available gradient High Performance Liquid Chromatography
equipment. The analytical method was developed in house using
modifications to published methods and then checked for linearity:
[0122] Linearity R2=1.0 [0123] Maximum percentile error=.+-.1%
[0124] Standards prepared from pure USP naproxen base were used for
comparison. Internal standards were not used, however the method of
standard additions was used on 3 samples to confirm the calibration
and ensure no interference from the background matrix.
Trial Details
[0125] All subjects were requested to fast for eight hours prior to
administration of the treatment then allowed to eat a normal
breakfast 1 hour later.
Each Subject Either:
[0126] placed a single buccal formulation according to the
invention in the cheek cavity or under the tongue, leaving it
undisturbed to disintegrate and release the active compound. Each
subject recorded the time taken for complete dissolution of the
buccal formulation; or [0127] ingested a single Naprogesic.RTM.
tablet with a minimum amount of water to aid swallowing.
[0128] After the treatments had been administered, the subjects
were allowed to eat. The first meal occurred one hour after
administration of the treatment. Around four and a half hours after
application of the treatment all the subjects had a light lunch.
Water, tea and coffee were taken during the seven-hour trial.
[0129] Blood samples were extracted from subjects over the
seven-hour period following application of the selected dosage
form. The blood was taken as individual extractions using normal
blood collection tubes and according to standard blood collection
protocols.
[0130] The tubes were mixed immediately after sampling and stored
refrigerated in preparation for processing the next day. Subsequent
repeat analysis confirmed that, once centrifuged and refrigerated,
plasma samples were stable for at least five days.
Data Analysis and Pharmacokinetic Parameter Estimations
[0131] Raw data was collected from the HPLC and processed via
integration. Chromatogram peak areas were utilised for
analysis.
[0132] The resulting figures were calculated in terms of ng
naproxen sodium per millilitre of blood plasma. The vacuum gel
tubes used to extract the blood are designed to draw the same
volume each time. To confirm this, the tubes were weighed prior to
centrifuging. The raw data was then subjected to Area under the
Curve analysis. This analysis produces figures for [0133] AUC;
[0134] C.sub.max; and [0135] T.sub.max
[0136] The AUC should be calculated from zero to a time at which
the concentration has returned to its regular levels. Also, when
making comparisons, one should insure that all AUC's are calculated
for the same time intervals.
[0137] To produce true comparative data, a mathematical procedure
was used to extrapolate the collected data for several additional
hours to give a total of twenty-four hours data. This extended data
was then re-analysed to give AUC.sub.24 figures for all
subjects.
[0138] The procedure used to extrapolate the data utilised the
quoted half-life of naproxen.
[0139] Simply, it was assumed that several hours post T.sub.max the
naproxen would decline essentially according to the half-life rule.
So, from the final tested point (at around seven hours) the decline
in the naproxen was theoretically calculated in line with regularly
documented half-life of 12 hours.
[0140] The resulting extrapolated curves were in line with the
actual test data.
Pharmacokinetic Data
[0141] Naproxen was detectable in plasma samples from all subjects
and was well within the detectable range of the test procedure.
[0142] Composite curves were constructed in order to collect all
data together. This was achieved by generating an average figure
for each time point within a group. These averaged time points were
then used to generate a composite curve that could be used as a
convenient visual comparison between the groups.
[0143] Previous work [14] indicated a near linear relationship
between the applied dosage and the response in terms of C.sub.max
and AUC. By making this assumption it is reasonable that the
response from the 275 mg tablet would be 2.75 times greater than
that from the 100 mg buccal formulation according to the invention.
To see this visually, an additional curve is included in the graph
that shows the result of multiplying the 100 mg buccal formulation
data by a constant factor of 2.75 (see FIG. 3).
Results and Discussion
[0144] A number of previous studies have examined the
pharmacokinetics of naproxen and its salt [6-15] and the ranges
reported concur with the results obtained in this study.
[0145] FIG. 1 illustrates simply that without any optimisation of
the buccal formulation a sustained and controlled release was
obtained, albeit slower in this case than the oral tablet
equivalent. With subsequent optimisation of the formulation, it
will be possible to shift the buccal formulation curve to the left
producing a T.sub.max at least equivalent to the tablet (in
vivo).
[0146] FIG. 2 shows raw comparative data (serum blood levels) for
100 mg naproxen base, 100 mg naproxen sodium and 275 mg
Naprogesic.RTM. tablet. In this unadjusted form, the indications
are that onset is equivalent for both salt preparations which were
also both superior to the naproxen base. As expected given the
higher tablet dose, the AUC value is lower for the naproxen sodium
buccal formulation. A Log graph of these results confirms that
conclusion.
[0147] Compared to the unadjusted raw data, FIG. 3 shows a
surprisingly very different picture. On a dose normalised basis,
the naproxen sodium buccal formulation delivered the active just as
quickly, but additionally produced a higher serum concentration of
the active, than the commercially available Naprogesic.RTM. tablet.
In addition, serum concentrations remained higher (AUC value)
indicating potentially a superior pain relief outcome. This pain
relief outcome was noted anecdotally by several trial subjects. The
naproxen base exhibited lower bioavailability and was not taken up
as quickly as expected given its poor solubility, but this should
not be construed as eliminating naproxen base from consideration as
a sustained pain relief product.
[0148] The dissolution profile indicates that an expected shift in
T.sub.max has been achieved in accordance with the invention. This
further indicates significant and exciting potential to take
optimisation further and improve the outcome given specific variant
changes to the formulation. There is a higher maximum concentration
and exposure (AUC) of naproxen sodium compared to naproxen base. On
a dose normalised basis, the naproxen buccal formulation exhibited
a higher C.sub.max and AUC.
[0149] There were no reported adverse reactions from buccal
administration of naproxen using this formulation and no
significant indication of patient non-compliance (membrane
irritation, throat catch or taste issues).
[0150] A significant majority of the anecdotal data suggested that
patients found this new formulation to be a significant improvement
over the original, and in some cases patients reported far longer
pain relief window lasting up to 8 hours.
[0151] When using the formulation according to the invention,
naproxen has been shown to be a suitable candidate for buccal
administration having a bioavailability at least equal to if not
superior to oral administration, with the advantage of bypassing
the gastrointestinal tract and therefore avoiding all the
associated side effects. Surprisingly, the results also suggest a
higher serum response with a rapid onset of action (with equivalent
dissolution) from a lower active dose compared to a three fold
larger oral dose.
REFERENCES
[0152] 1. Martindale, The Complete Drug Reference, Pharmaceutical
Press London, 35.sup.th Edition, 2007 p 78. [0153] 2. Runkel R et
al, J Pharm Sci., 61: (5) pp 703-708 (1972). [0154] 3. Place V,
Darley P et al., Clin Pharmacol Theor vol 43, No 3, (March 1988)
[0155] 4. Amaral M H, Lobo J M S et al. AAPS Pharm Sci/Tech, 2001
2(2) article 6. [0156] 5. Bhise K S et al, AAPS PharmSciTach; 8(2),
Article 44 (2007). [0157] 6. Carmen Carrasco M, Herrera J E et al.
Arznelm-Forsch/Drug Res. 56, No 8, 589-592 (2006). [0158] 7.
Aarbakke J, Gadeholt G and Hoylanskjaer A, International Journal of
Clinical Pharmacology Therapy and Toxicology, Vol 21, No 6,
281-283, (1983). [0159] 8. Desage J P et al., Journal of Clinical
Pharmacology pp 189-193 (April 1976). [0160] 9. Vree T B et al,
Biopharmacokinetics and Drug Disposition, Vol 14, pp 491-502
(1993). [0161] 10. Sastry M S P and Diwan P V., Arznelm-Forsch/Drug
Res 43 (II) No 11 (1993). [0162] 11. Charles B G and Mogg G A G,
Biopharmacokinetics and Drug Disposition Vol 13, pp 121-128 (1994).
[0163] 12. Marzo A et al, Arznelm-Forsch/Drug Res 47 (I), pp
385-389, (1997) [0164] 13. Diansong Zhou et al, J Clin Pharmacol,
38, pp 625-629 (1998). [0165] 14. Niazi S K et al,
Biopharmacokinetics and Drug Disposition, Vol 17, pp 355-361
(1996). [0166] 15. Strocchi et al, International Journal of
Clinical Pharmacology, Therapy and Toxicology, Vol 29 No 7 pp
253-256, (1991). [0167] 16. Bourke D L, Smith T C. "Estimating
allowable hemodilution". Anesthesiology. 1974; 41: 609-612. [0168]
17. Hamman, Josias H. "Chitosan Based Polyelectrolyte Complexes as
Potential Carrier Materials in Drug Delivery Systems" Mar. Drugs
2010, 8: 1305-1322.
Example 2
[0169] Examples of formulations containing ibuprofen as the active
compound according to the invention were prepared as follows (the
proportions are all percentage by weight).
Formulation 1
TABLE-US-00002 [0170] Active Ibuprofen lysine at 20% which is
equivalent to 100 mg Throat Catch agent Carbomer 934P (971P or
974P) at 0.5-5% Miraculin at 2% Flavour Spearmint at 2% Complexing
Hyaluronic acid at 20% Agent/enhancer Permeation Enhancer
Lysalbinic acid 0.5% Disintegrant and Aluminium hydroxide at 1-2%
and Sodium masking agent bicarbonate at 1% Binder/Filler Sorbitol
at up to 42% but adjust to make up 100% (32-56%) Flow Agent
Magnesium hydroxide at 2-5%
Formulation 2
TABLE-US-00003 [0171] Active Ibuprofen arginine at 20% which is
equivalent to 100 mg Throat Catch agent Mixture of arginine with
citric acid, oleic acid and glutamic acid at 1-10% Flavour
Spearmint at 2% Complexing Agent PEG 3500 at 20% Permeation
Enhancer Powdered ethanol (commercial product) at 0.5-1.0%
Disintegrant and Sodium bicarbonate at least 1% masking agent
Binder/Filler Erythritol at up to 42% but adjust to make up 100%
(32-56%) Flow Agent Magnesium hydroxide or aluminium hydroxide at
5%
Formulation 3
TABLE-US-00004 [0172] Active Sodium ibuprofen dihydrate at 20%
which is equivalent to 100 mg Throat Catch agent Carbomer 934P at
0.5-5% Flavour Spearmint at 2% Release Agent PEG 4000 at 25%
Permeation Enhancer Sorbitol at 5% Disintegrant and Sodium
bicarbonate at least 2% masking agent Mannitol at least 2%
Binder/Filler Erythritol at up to 42% but adjust to make up 100%
(32-56%) Flow Agent Magnesium stearate at up to 3%
Example 3
[0173] This example investigates the pharmacokinetic analysis of
plasma ibuprofen concentration versus time profiles for different
ibuprofen formulations.
Methods
[0174] A clinical trial was conducted to obtain a results
appropriate for statistical analysis. The methodology used in this
Example was the same as that used in Example 1, except that there
were 11 subjects.
Treatments
[0175] 1 Oral ibuprofen lysine (342 mg, equivalent to 200 mg
ibuprofen; Nurofen.RTM. Back Pain). (equivalent compound in a
swallow formulation) [0176] 2 Oral Sodium ibuprofen dihydrate (256
mg; equivalent to 200 mg ibuprofen; Nurofen.RTM. Zavance.RTM.).
(equivalent compound in a swallow formulation) [0177] 3 Sublingual
ibuprofen sodium Linguet.TM. formulation 50 mg (equivalent to 50 mg
ibuprofen). This formulation was prepared according to the
disclosure in WO 2006/105615. [0178] 4 Sublingual ibuprofen sodium
Linguet.TM. formulation 100 mg (equivalent to 100 mg ibuprofen).
This formulation was prepared according to the disclosure in WO
2006/105615. [0179] 5 Sublingual ibuprofen lysine Linguet.TM.
Eureka formulation (equivalent to 50 mg ibuprofen). This
formulation was prepared according to the invention. [0180] 6
Sublingual ibuprofen lysine Linguet.TM. Hewitt formulation
(equivalent to 50 mg ibuprofen). This formulation was prepared
according to the invention.
[0181] The sublingual formulations are described in more detail in
the tables below.
TABLE-US-00005 Ibuprofen sodium Linguet .TM. formulation 50 mg
Excipient Amount (mg) % total Ibuprofen sodium 61.56 8.1 Magnesium
stearate 15 2.0 Sorbitol 408 53.9 Lactose 150 19.8 Stevia 3.75 0.5
PEG 3350 112.5 14.9 Sodium bicarbonate 3.75 0.5 Citric Acid 1.5 0.2
Black currant 1.5 0.2 Total weight 757.56 100.0
TABLE-US-00006 Ibuprofen sodium Linguet .TM. formulation 100 mg
Excipient Amount (mg) % total Ibuprofen sodium 123.12 27.8 Carbomer
9 2.0 Lecithin 36 8.1 Spearmint 9 2.0 Stevia 6 1.4 PEG 3350 60 13.6
Ethanol powder 3 0.7 Methyl cellulose 22 5.0 Sodium bicarbonate 3
0.7 Erythritol 150 33.9 Magnesium hydroxide 6 1.4 Aluminum
hydroxide 15 3.4 Total weight 442.12 100.0
TABLE-US-00007 Ibuprofen lysine Linguet .TM. Eureka formulation
Excipient Amount (mg) % total Ibuprofen lysine 85.5 22.0 Carbomer
Throat catch 9 2.3 Lecithin agents 36 9.3 Spearmint Tastemasking 9
2.3 Stevia agents 6 1.5 PEG 3350 60 15.4 Ethanol powder 3 0.8
(permeation enhancer) Methyl cellulose 22 5.7 Sodium bicarbonate 3
0.8 Erythritol 140 36.0 Magnesium hydroxide Buffering 7.5 1.9
Aluminum hydroxide agents 7.5 1.9 Total weight 388.5 100.0
TABLE-US-00008 Ibuprofen lysine Linguet .TM. Hewitt formulation
Excipient Amount (mg) % total Ibuprofen lysine 85.5 10.9 Magnesium
stearate 15 1.9 Sorbitol 408 52.2 (permeation enhancer) Lactose 150
19.2 Stevia (taste 3.75 0.5 masking agent) PEG 3350 112.5 14.4
Sodium bicarbonate 3.75 0.5 Citric acid 1.5 0.2 Blackcurrant 1.5
0.2 Total weight 781.5 100.0
[0182] The individual and group mean data was transferred into
WinNonLin Pro Node 5.2.TM. and subjected to pharmacokinetic
analysis. The following pharmacokinetic parameters were calculated
for the individual and group mean data: area under the curve (AUC);
terminal phase elimination rate constant (.lamda.z); maximum
concentration (C.sub.max); time to reach maximum concentration
(T.sub.max); and terminal half life (T.sub.1/2). Pharmacokinetic
parameters were calculated using a noncompartmental analysis (NCA)
model. A uniform weighting scheme was used for the determination of
the elimination rate constant and half-life. AUC values for the
plasma ibuprofen concentration profiles were calculated using the
linear trapezoidal rule up to the last measurable sampling time
point (AUC.sub.0-last) and extrapolated to infinity
(AUC.sub.(0-inf)).
[0183] The following parameters were then calculated for the mean
dose normalised values. [0184] AUC.sub.(O-inf) Area Under Curve
extrapolated to infinity. [0185] C.sub.max (ng/ml) Maximum
concentration [0186] T.sub.max (hr) Time to reach maximum
concentration
Results
[0187] The ibuprofen concentration versus time profiles for the
differing formulations show similar kinetics with a fast increase
in concentration up to a maximum and then a relatively slower
decrease in concentration over time. The most marked differences
between the formulations are observed in the AUC values. FIGS. 6
and 7 provide a visual representation of the C.sub.max and AUC
results.
TABLE-US-00009 Zavance .RTM. Nurofen .RTM. IB IB Lysine IB Lysine
Mean Dose Sodium IB Back Pain Sodium 50 Mg 50 Mg Normalised
dihydrate IB Lysine 50 Mg Linguet .TM. Linguet .TM. Values 256 Mg
342 Mg Linguet .TM. (Hew) (Eureka) C.sub.max 13.80 17.75 15.00
26.80 23.10 T.sub.max 1.00 0.50 1.00 0.50 1.00 AUC(0-inf) 39.29
42.51 47.61 84.41 80.87
CONCLUSION
[0188] FIGS. 6 and 7 clearly illustrate that the two ibuprofen
lysine formulations according to the invention had significantly
better pharmacokinetics than either of the formulations according
to WO 2006/105615 or the current oral formulations (Nurofen.RTM.
Back Pain and Zavance.RTM.). Further, these improved
pharmacokinetics are with respect to an earlier onset of action and
release over an extended period of time. In addition, these results
were achieved using a lower dose and were in line with the
optimised graphical representation as depicted in FIG. 8 (ie a
predetermined release rate).
[0189] In addition to the improved control over the
pharmacokinetics provided by complexing agents and membrane
permeability enhancers, the use of taste masking agents (which deal
with throat catch, buffering and flavour) was reported by trial
subjects to significantly improve mouthfeel and virtually eliminate
throat catch and taste issues. These qualitative elements emerge as
significant commercial drivers when patient compliance with any
formulation to be taken into production is considered.
Example 4
[0190] In this example, a formulation is developed according to the
invention for venlafaxine hydrochloride (an antidepressant).
TABLE-US-00010 Excipient Amount (mg) % total Venlafaxine
hydrochloride 75 12.0 (equivalent to 75 mg) Carbomer 10 1.6
Benecoat .TM. 40 6.4 Coffee/vanilla extract 10 1.6 Stevia 8 1.3 PEG
3350 90 14.4 Ethanol powder 4.5 0.7 Methyl cellulose 30 4.8 Sodium
bicarbonate 4 0.6 Erythritol 140 22.3 Sorbitol 200 31.9 Magnesium
hydroxide 7.5 1.2 Aluminium hydroxide 7.5 1.2 Total weight 626.5
100.0
[0191] The aim of this formulation is to provide a faster speed of
onset with an equivalent or slightly lower C.sub.max but with a
significantly higher AUC value or therapeutic treatment window than
the extended release formulation disclosed in AU2003259586
(equivalent compound in a swallow formulation). AU2003259586 has
been used as a commercial reference and as a basic indicator of
what optimisation potential should be expected through using this
invention.
[0192] The superior AUC will be evidenced by a longer "tail" on the
plasma concentration vs. time curve. FIG. 9 depicts a graphical
representations of the results from AU2003259586 and FIG. 10
illustrates what is expected to be achieved using a formulation
according to the invention (ie a predetermined release rate).
[0193] FIG. 10 indicates that an expectation of delivering a
superior outcome off a significantly lower dose (75 mg once daily)
is possible using an optimal variant of the above formulation. The
implications for patient compliance (once daily dose with no
side-effects) are very positive.
Example 5
[0194] This is a further example of a formulation according to the
invention containing melatonin as the active compound.
TABLE-US-00011 Excipient Amount (mg) % total Melatonin* 2.5 2.8
Magnesium stearate 1.3 1.4 Sorbitol 65 72.5 Stevia 2.5 2.8 PGA Base
B 10.5 11.7 Ethanol powder 3 3.3 Citric acid 0.4 0.4 Sodium
bicarbonate 0.5 0.6 Plasdone S630 4 4.5 Total weight 89.7 100.0
*note equivalent to 10.2 mg theoretically active concentration
[0195] This formulation has been prepared in several preliminary
batches used to confirm tabletting procedures, release rates and
dissolution times. This formulation has a dissolution time of 24
minutes measured using a standard dissolving test (roller method,
using a belt roller apparatus).
[0196] Although no plasma concentration studies have been completed
with this formulation, the inventors anticipate that a similar
result (Linguet.TM. vs. oral dose) as those shown in the examples
above will be achieved. That is, a superior treatment window
(higher AUC dose normalised value) generated using a lower dose
with a correspondingly more patient compliant safety profile.
Example 6
[0197] Formulations according to the invention containing sterolin
as the active compound were prepared.
Formulation 1
TABLE-US-00012 [0198] Excipient Amount (mg) % total Sterolin* 5
10.0 Magnesium stearate 1 2.0 Sorbitol 37.5 75.0 PGA Base B 4.5 9.0
Plasdone S630 2 4.0 Total Weight 50 100.0 *note equivalent to a
theoretical active concentration of 22.0 mg
[0199] This formulation has a dissolution time of 48 minutes
measured using a standard dissolving test (roller method, using a
belt roller apparatus).
Formulation 2
TABLE-US-00013 [0200] Excipient Amount (mg) % total Sterolin* 2.5
5.0 Magnesium stearate 1 2.0 Sorbitol 35 70.0 PGA Base B 9 18.0
Citric acid 0.25 0.5 Plasdone S630 2 4.0 Sodium bicarbonate 0.25
0.5 Total Weight 50 100.0 *note equivalent to a theoretical active
concentration of 22.5 mg with half the dissolution time
[0201] This formulation has a dissolution time of 24 minutes
measured using a standard dissolving test (roller method, using a
belt roller apparatus).
Example 7
[0202] A formulation according to the invention containing
ibuprofen lysine in combination with cetirizine (antihistamine) as
the active compounds was prepared.
TABLE-US-00014 Ibuprofen lysine/cetirizine Linguet .TM. formulation
Excipient Amount (mg) % total Ibuprofen lysine 85.5 22 Cetirizine 1
2 Carbomer Throat catch 9 2.4 Lecithin agents 36 9.3 Spearmint
Taste masking 9 2.3 Stevia agents 6 1.5 PEG 3350 60 15.4 Ethanol
powder 3 0.8 (permeation enhancer) Methyl cellulose 22 5.7 Sodium
bicarbonate 3 0.8 Erythritol 140 36.0 Magnesium hydroxide Buffering
7.5 1.9 Aluminum hydroxide agents 7.5 1.9 Total weight 389.5
100.0
[0203] The projected dissolution time for this formulation is 15-20
minutes to be measured using a standard dissolving test (roller
method, using belt roller apparatus).
Example 8
[0204] A formulation according to the invention containing
glucosamine as the active compound was prepared.
TABLE-US-00015 Excipient Amount (mg) % total Glucosamine 265.2 51
Magnesium stearate 7.8 1.5 Sorbitol 119.6 23 Hyaluronic acid 57.2
11 Caramel flavour 2.6 0.5 Plasdone S630 26 5 Ethanol powder 41.6 8
Total weight 520 100.0
[0205] A 520 mg Linguet.TM. will deliver a theoretically active
conc. around 260 mg This formulation has a dissolution time of 29
minutes measured using a standard dissolving test (roller method,
using a belt roller apparatus).
[0206] The word `comprising` and forms of the word `comprising` as
used in this description and in the claims does not limit the
invention claimed to exclude any variants or additions.
[0207] Modifications and improvements to the invention will be
readily apparent to those skilled in the art. Such modifications
and improvements are intended to be within the scope of this
invention.
* * * * *